The long term goal of the proposed study is to provide a better understanding of the mechanisms responsible for the organ failure that occurs during endotoxin shock. Through this, it is hoped that a more effective therapeutic means can be developed for the treatment of septic shock. Death in the U.S. due to septicemia has increased 700% since 1950 and over 25% during the last reporting period from 1979 to 1981 (U.S. Dept. of Health and Human Resources). Previous work in this and other laboratories has demonstrated that endogenous angiotensin II plays a major role in the maintenance of mean arterial pressure (MAP) during endotoxin shock. Based upon the known actions of this compound, it is suggested that this elevation of MAP is accomplished by vasoconstriction which would further reduce blood flow to various vascular beds, thus increasing shock induced tissue damage. Unfortunately, blockade of angiotensin II (either formation or at receptor sites) drastically lowers MAP and has failed to produce beneficial effects. This is presumable due to depressed blood flow to the brain and heart secondary to the lower MAP. The current study proposes to investigate the effect of angiotensin II blockade upon tissue ATP levels and regional blood flow during endotoxin shock. ATP levels will be determined with the luciferin-luciferase assay on tissue collected using the in situ freeze clamp technique. Regional blood flow will be determined using radioactive microspheres. These values will be compared to similar values determined for animals given only saline and to those given only endotoxin. Additional studies will determine if various drugs reported to produce beneficial effects in shocked animals (naloxone, ibuprofen, or methylprednisolone) can improve organ blood flow and tissue ATP levels in animals given endotoxin with and without angiotensin blockade. The animals will be ventilated with room air so as to maintain an end-tidal CO2 of 5.0 plus/minus 0.5%. The arterial pressure and EKG will be recorded and from these tracings, MAP, pulse pressure and heart rate will be calculated. All experiments will be conducted using anesthetized adult mongrel dogs. The animals will be anesthetized (pentobarbital) prior to any invasive procedures and will not be allowed to regain consciousness. Appropriate statistical analysis will be used to compare and evaluate the experimental data.
|Leffew, S D; Williams, C D; Janssen, H F (1987) Cardiorespiratory alterations produced by centrally administered thyrotropin-releasing hormone during canine endotoxin shock. Circ Shock 21:225-32|